Abstract 5132: Lactic acidosis-mediated transcriptomic and metabolomic rewiring in pancreatic cancer cells

Abstract

Abstract Tumor microenvironment plays a critical role in regulating tumor cell metabolism and progression. The tumor cells are constantly exposed to hypoxia, nutrient starvation, and extracellular acidification that contribute to tumor malignancy. These malignant cells exhibit Warburg effect by maintaining glycolytic phenotype even in the presence of oxygen and excrete lactate and protons via monocarboxylate transporters, and sodium-hydrogen antiporter 1 (NHE1) causing constant acidification of the tumor microenvironment. The tumor cells must thus adapt to acidosis to thrive in such hostile microenvironment. The purpose of the study is to identify the functional response of pancreatic cancer cells to the acidic tumor microenvironment. We performed integrated transcriptomic and metabolomic analyses to identify the existence of low pH-responsive transcriptional and metabolic regulators. Culturing the cells under low pH resulted in a reduction in cell growth and an increase in oxidative stress within the cells. RNA-seq-based transcriptomic analyses revealed that acidosis drives distinct gene expression patterns in PDAC cells with the expression of 499 and 496 genes up- and downregulated, respectively in PDAC cells. GSEA analyses of significantly modulated genes identified pathways including cell cycle, DNA repair, metabolic pathways, ABC transporters, glutathione metabolism, and genes involved in signaling cascades such as the inositide signaling pathway. As the transcriptomic analyses showed an enrichment of metabolic genes, intracellular metabolomic analyses revealed that chronic acidosis leads to a shift in cellular metabolism towards oxidative metabolism. Our studies demonstrate that while chronic acidosis in the tumor microenvironment leads to reduced proliferation and glycolysis in tumor cells, it also results in increased expression of genes involved in cellular migration, signaling pathways and switching to anaplerotic glutamine metabolism in response to an acidic tumor microenvironment. Overall, our studies demonstrate metabolic reprogramming in PDAC cells in response to low pH microenvironments creating a metabolic vulnerability that could be exploited for therapeutic targeting of pancreatic cancer. Citation Format: Divya Murthy, Jaime Abrego, Ryan James King, Pankaj Kumar Singh. Lactic acidosis-mediated transcriptomic and metabolomic rewiring in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5132.